Gliomas represent over half of all brain cancers and are by far the most common type of primary brain tumor in adults. Glioblastoma multiforme (GBM), the most common form of glioma, is associated with dismal clinical prognosis. GBM patients presenting with GBM often have survival rates as low as one year, even after surgical resection of the tumor and combined chemo and radiotherapy. As an example of the unmet therapeutic need for this tumor type, the alkylating agent temozolomide is one of the only chemotherapeutic agents with a proven survival benefit, only extending life by approximately three months. To date, most brain tumor research has focused on the genetics and biochemical signaling pathways unique to tumor cells. In all cancer types, however, it is becoming greatly appreciated how microenvironmental factors contribute to tumor cell behavior. During GBM progression, many changes occur in the tumor microenvironment, including recruitment and remodeling of tumor-associated vasculature, extensive hypoxia, and immune cell infiltration, all of which likely drive the robust invasive and treatment-resistant characteristics of GBM cells. The recent discovery of a vascular niche that not only harbors tumor stem cells but also provides essential signals for self-renewal and maintenance provides evidence that tumor cell propagation and aggressiveness is strongly influenced by contextual signals emanating from the tumor microenvironment. In addition, brain tissue of GBM patients is associated with large changes in mechanical forces. This includes dramatic increases in intracranial pressure as well as stiffening of tumor tissue. The latter is likely a result of increased tumor cell contractility, extracellular matrix deposition and modifications. Perturbations in such cell- intrinsic and extrinsic forces have been shown to drive the malignant phenotype in several epithelial cancers;however the role of mechanical forces in brain cancer progression has largely been overlooked. My proposed studies intend to reveal how the vascular niche, its inflammatory cell constituents, and its associated ECM affect tumor stem cell survival, migration, and proliferation. Further, this proposed work will directly test the effect of perturbed microenvironmental force on tumor cell aggressiveness and GBM progression. This will be done systematically by closely monitoring tumor cell behavior and tumor progression in novel mouse modes of glioma exhibiting either augmented or attenuated integrin signaling, focal adhesion formation, or cell contractility. Furthermore, this work aims to address the question of whether GBM arises from a neural stem cell precursor, as is often debated. These mouse studies will make use of histology, biochemistry, molecular imaging techniques, as well as quantitative measurements of the mechanical properties of cells and tissues. To reveal cell-cell interactions important in GBM progression, I aim to establish a live animal imaging technique allowing real time visualization of tumor and vascular cells. Ultimately, these studies aim to elucidate the relative contributions of the mechanically challenged brain microenvironment to tumor cell aggressiveness and survival during glioma progression. Progress in this underdeveloped area will be important to reveal new and more successful avenues for brain tumor therapy.

Public Health Relevance

Surgery and chemotherapy are often unsuccessful in glioma patients, who on average exhibit dismal survival rates. Because the role of mechanical forces in glioma cell behavior has not been directly investigated, these proposed studies are of great importance. The proposed studies will lead to identification of the mechanically- sensitive signaling pathways that are activated in response to changes in the microenvironment during glioma progression. This will potentially lead to discovery of novel therapies for brain cancer patients who often have elevated intracranial pressure and tissue stiffness. The findings that perturbed microenvironmental forces drive the malignant phenotype in mammary and pancreatic carcinoma support the rationale for my studies and provide me with confidence that our findings will be of significance.